Predisposition to Addiction: Pharmacokinetics, Pharmacodynamics, and Brain Circuitry

There is now little doubt that the development of addiction to drugs of abuse is, in part, a function of predisposing factors in an individual’s genome as well as factors associated with childhood and adolescent development. As much as drugs of abuse have profound pharmacological consequences on neuronal physiology, it is clear that while these drug actions are necessary, they are not sufficient for the development of addiction. When one compares the widespread recreational use of addictive drugs and the substantially fewer individuals meeting DMS-IV criteria for substance abuse disorder, it is apparent that drug pharmacology is only one factor in a multifactorial gene-environment-pharmacologic disorder. The search for the factors producing addiction and, more specifically, those factors that mediate the transition from recreational to compulsive (addicted) drug use has proceeded at all levels of investigation, from gene polymorphisms to sociological interventions.

Exploring the factors causing addiction has primarily involved examining addicts for neurobiological and genetic differences from comparison subjects lacking a substance abuse disorder who are matched according to a variety of other biological, diagnostic, and sociological criteria. In this issue of the Journal, three research reports reflect different aspects of this research tactic. The article by Little et al. is indicative of perhaps the most traditional approach. As in many studies, postmortem tissue obtained from the caudate of cocaine addicts and matched comparison subjects was compared for protein content or function. This is an extension of many previous investigations that have hypothesized neuroadaptations in the proteins associated with the pharmacodynamic action of cocaine on dopamine transmission (1), pointing toward nigrostriatal dopamine depletion or perhaps a lesion in the caudate of addicts. Little et al. employ an arguably more definitive measure: the immunoreactive level of the central vesicular monoamine transporter protein (VMAT2) was used to verify that cocaine addicts have less of this critical enzyme for concentrating dopamine in synaptic vesicles. The authors recognize this as a pharmacological effect of heavy cocaine abuse and make no speculations as to whether this alteration is related to a predisposition for addiction or is even a marker of compulsive versus recreational cocaine use. However, as the authors note, it is likely that the down-regulation of VMAT2 is associated with high levels of recent drug use, since animal studies that do not involve the levels of drug administration typically observed in severe cocaine addicts do not show enduring alterations in the basal levels of any metric of dopamine transmission. The authors did, however, find hints of a predisposing or associated factor in that the capacity of cocaine to reduce VMAT2 was potentially more profound in addicts with associated mood disorder. Nonetheless, the research tactic of examining postmortem brain tissue for proteins directly associated with the pharmacological effects of the drug, while likely to yield drug-mediated differences, cannot assess the role of the neurobiological adaptation as a predisposing factor or even as an important factor in maintaining addiction. A primary reason for this lack of certainty can be found in the animal literature, where drug-induced changes in protein expression or function have been shown to depend on the time of sampling and to vary during drug administration and withdrawal. The general inability of postmortem studies in addicts to determine the length of abstinence or to sample at different points in the sequelae of drug taking, withdrawal, and craving severely limits the capacity to interpret the relationship between the pharmacodynamics of the drug and factors that predispose to or maintain addiction.

A second paper in this issue of the Journal by Wall et al. is indicative of a widely used and potentially more profitable approach toward identifying predisposing factors in alcohol addiction. These authors studied a population of Native North American Indians to examine alcohol and aldehyde dehydrogenase polymorphisms as pharmacokinetic predisposing factors in alcoholism. Reminiscent of previous studies that have established that polymorphisms in one aldehyde dehydrogenase gene contribute strongly to reduced alcohol consumption and addiction in Asian populations (2), these authors demonstrate that polymorphisms in one of the alcohol dyhydrogenase genes is a predisposing factor in alcoholism in Native Americans. Not only does this information link a specific enzyme to alcohol dependence, but it confirms the utility of examining discrete populations with high levels of addiction as a mechanism for identifying important but relative uncommon polymorphisms.

Although it is tempting to generalize findings between addictive substances, pharmacokinetic predispositions will not generally cross between drug classes where different catabolic or bioactivating enzymes are involved. In contrast, another research tactic has emerged over the last few years that can potentially identify common predisposing factors between different addictive substances. This tactic is based upon a deepening reservoir of neurophysiological knowledge regarding the functional brain circuits that mediate the physiological and pathological acquisition of environmental reinforcement, ranging from food and sex to gambling and addictive drugs (3). The most relevant information in this regard has emerged from increasingly sophisticated neuroimaging studies that point directly to the importance of interconnections between prefrontal and allocortical limbic brain regions and subcortical motor systems in addiction to all drugs of abuse examined. The third paper in this issue of the Journal combines this neurophysiological database with cognitive testing to probe whether poor performance in a decision-making task may be a shared trait between a population of adolescents known to be prone to developing addiction and adults meeting criteria for substance abuse disorder. Ernst et al. discovered that adolescents with externalizing behavioral disorders, including ADHD and conduct disorder, and adult addicts both performed poorly on aspects of repeated testing with the Gambling Task. On the basis of this finding, it is possible that a shared neurophysiological dysfunction may exist between drug addicts and adolescents with externalizing behavioral disorders, and poses the possibility that this may be a predisposing cognitive characteristic. While the authors identify many appropriate caveats to accepting this conclusion, the data point to important future studies that could combine neuroimaging with decision-making performance in the Gambling Task between these two populations. Such cognitive probes of neural circuitry combined with populations vulnerable to addictive disorders constitutes an experimental design that might reveal common circuitry dysfunctions that can begin to define a common pathological basis of predisposition to addiction. The potential for distinctions in brain circuitry to underlie predispositions in vulnerable populations stands in contrast to the pharmacokinetic or pharmacodynamic properties of individual drugs.